A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice
- Authors
- Min, Hye Sook; Lee, Ji Eun; Ghee, Jung Yeon; Kang, Young Sun; Cha, Jin Joo; Han, Jee Young; Han, Sang Youb; Cha, Dae Ryong
- Issue Date
- 3월-2021
- Publisher
- MDPI
- Keywords
- cyclosporine nephrotoxicity; DPP-4; DA-1229; inflammation; fibrosis; oxidative stress
- Citation
- LIFE-BASEL, v.11, no.3, pp.na
- Indexed
- SCIE
SCOPUS
- Journal Title
- LIFE-BASEL
- Volume
- 11
- Number
- 3
- Start Page
- na
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/128522
- DOI
- 10.3390/life11030251
- ISSN
- 0024-3019
- Abstract
- Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.
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